Coding and processing of error signals in inferior olivary-cerebellar networks

下橄榄小脑网络中误差信号的编码和处理

• 批准号: 8448783
• 负责人: JAVIER F MEDINA
• 金额: $ 37.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-02 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448783
• 关键词: Accounting; Action Potentials; Address; Air; Animals; Attention deficit hyperactivity disorder; Autistic Disorder; Automobile Driving; Axon; Blinking; Brain; Cerebellum; Code; Cornea; Coupling; Detection; Electrodes; Equation; Event; Eye; Failure; Fiber; Frequencies; Future; Genetic; Goals; Golf; Hearing; Image; Impairment; Individual; Inferior; Knockout Mice; Knowledge; Learning; Link; Mediating; Memory; Monitor; Motor; Movement; Mus; Mutant Strains Mice; Neurons; Olives - dietary; Outcome; Pathway interactions; Pattern; Performance; Population; Probability; Problem Solving; Process; Property; Recording of previous events; Research; Role; Schizophrenia; Side; Signal Transduction; Stimulus; Symptoms; Testing; Time; Trigeminal Nuclei; Uncertainty; Update; Work; awake; base; classical conditioning; conditioning; connexin 36; electrical microstimulation; expectation; improved; microstimulation; motor control; motor learning; nervous system disorder; neural circuit; neural patterning; novel strategies; optogenetics; relating to nervous system; research study; response; statistics; theories; tool; two-photon

DESCRIPTION (provided by applicant): We learn from our mistakes. The goal of this project is to understand how the errors that drive learning are encoded and processed in the brain. All experiments are done using eyeblink conditioning, a simple form of associative learning that offers a number of advantages: 1) Errors are under experimental control and can be easily manipulated. In eyeblink conditioning, subjects learn to blink and protect the eye from a corneal air-puff that is applied every time after they hear a tone. Error, defined as the discrepancy between the real air-puff and what the subject expected, can be manipulated simply by unexpectedly changing the strength of the air-puff on any given trial. 2) Eyeblink conditioning can be done in mice. This opens up the door for approaches that take advantage of genetic tools to investigate the neural basis of error processing in awake-behaving animals. 3) The neural circuits mediating eyeblink conditioning have been identified previously. Knowledge about the connectivity of these circuits has led to the hypothesis that neurons in the inferior olive generate error signals by comparing information about the real air-puff, presumably conveyed to the inferior olive via an excitatory pathway from the trigeminal nucleus, and the expected air-puff, presumably conveyed via an inhibitory cerebellar pathway. This project uses the 3 advantages listed above to investigate the role of errors in eyeblink conditioning, and to elucidate the coding and processing of error signals by neurons in the inferior olive. Specific aim 1 challenges the widely-held view that to update expectations (about the strength of future air- puffs, for example), the brain takes into account only the error in the current trial. By unexpectedly changing the strength of the air-puff trial-by-trial, this aim will define the role of history and statistics of prior errors in updating expectations about future events. Specific aim 2 is about deciphering the neural code used by neurons in the inferior olive to represent errors of different sizes. By doing eyeblink conditioning in mice, while recording single-units and imaging populations of neurons in the inferior olive, this aim will reveal whether synchrony provides information about the size of the error in single trials. Specific aim 3 takes advantage of genetic tools to ask if synchrony in the inferior olive is necessary and/or sufficient to represent the error signal and drive eyeblink conditioning. Whether synchrony is necessary will be addressed by assessing eyeblink conditioning in connexin36 mice, whose activity in the inferior olive is normal except for reduced levels of synchrony due to loss of electrotonic coupling. Whether synchrony is sufficient will be addressed using optogenetic stimulation in mice expressing channelrhodopsin in the inferior olive, and assessing the efficacy with which different spatio-temporal patterns of neural activation can signal error to drive eyeblink conditioning.

描述（由申请人提供）：我们从错误中吸取教训。该项目的目标是了解驱动学习的错误如何在大脑中编码和处理。所有实验都是使用眨眼条件反射完成的，这是一种简单的联想学习形式，具有许多优点：1）误差处于实验控制之下，并且可以轻松操纵。在眨眼调节中，受试者学习眨眼并保护眼睛免受每次听到声音后施加的角膜吹气的影响。误差被定义为真实的吹气与受试者预期之间的差异，可以通过在任何给定的试验中意外地改变吹气的强度来控制。 2）眨眼调节可以在小鼠身上进行。这为利用遗传工具研究清醒动物错误处理的神经基础的方法打开了大门。 3）先前已经确定了介导眨眼条件反射的神经回路。关于这些回路连接性的知识导致了这样的假设：下橄榄核中的神经元通过比较真实吹气的信息（可能通过从三叉神经核的兴奋性通路传递到下橄榄核）和预期的空气来产生错误信号-puff，大概是通过抑制性小脑通路传递的。该项目利用上面列出的 3 个优点来研究错误在眨眼条件反射中的作用，并阐明下橄榄神经元对错误信号的编码和处理。具体目标 1 挑战了广泛持有的观点，即为了更新期望（例如，关于未来吹气的强度），大脑仅考虑当前试验中的错误。通过一次又一次地出人意料地改变吹气的强度，这一目标将定义历史记录和先前错误的统计数据在更新对未来事件的预期中的作用。具体目标 2 是破译下橄榄神经元使用的神经代码来表示不同大小的错误。通过对小鼠进行眨眼条件反射，同时记录下橄榄神经元的单个单元和成像群体，这一目标将揭示同步性是否提供了有关单次试验中误差大小的信息。具体目标 3 利用遗传工具来询问下橄榄核中的同步是否必要和/或足以表示误差信号并驱动眨眼调节。同步是否必要将通过评估 connexin36 小鼠的眨眼条件来解决，其下橄榄的活动正常，除了由于电紧张耦合损失导致同步水平降低之外。同步是否足够将通过在下橄榄表达通道视紫红质的小鼠中使用光遗传学刺激来解决，并评估神经激活的不同时空模式可以发出错误信号以驱动眨眼调节的功效。